Many important variables in biomedical studies of HIV/AIDS are ordered categorical. A few examples include WHO clinical stage, level of education, frequency of douching, stage of cervical lesions, self- reported condom use, and biallelic genotypes. Although ordinal variables are common, statistical methods that account for their ordered nature are lacking, particularly when the ordinal variable is a predictor variable. Most standard methods either treat the ordinal predictor as categorical (ignoring the order information) or continuous (making linearity assumptions). This proposal develops statistical methods that account for the ordered nature of ordinal variables without making linearity assumptions. The methods address situations when a predictor variable (X) is ordered categorical; the outcome variable (Y) is continuous, discrete, counts, time-to-event, or repeated measures; and there are multiple covariates (Z). The general approach is to fit appropriate regression models of Y on Z, and X on Z, and then to test for correlation between the residuals from these two models. The methods therefore rely on a new definition of residual for ordered categorical data. Statistical properties of this residual are evaluated, as well as its use in model diagnostics. Asymptotic properties of the residual- based test statistics are computed, relationships with other methods are derived, user-friendly software that implements these methods is developed, and the advantages of the new methods are studied using simulated and real data. The methods are applied to two HIV studies: The first assesses the effect of the frequency of douching on sexually transmitted infections among a cohort of adolescent females using marginal structural models. The second data application looks for human genetic polymorphisms associated with drug plasma levels, virologic failure, and toxicities for patients initiating an efavirenz- or abacavir-based antiretroviral regimen. PUBLIC HEALTH RELEVANCE: The new methods are put into computer software and applied to studies of 1) the effect of douching on sexually transmitted infections among adolescent females, and 2) which patients may be able to better respond to specific HIV-treatments based on genetic patterns.